Wave Life Sciences - Earnings Call - Q4 2024

Executive Summary

• Q4 2024 returned to profitability as collaboration revenue recognition drove revenue to $83.7M and net income to $29.3M; cash ended at $302.1M with runway into 2027. CFO noted the quarter’s step-up was “primarily” from recognition of deferred revenue under the Takeda collaboration.
• Clinical execution advanced across programs: dosing ongoing in INLIGHT (WVE-007, obesity; initial data 2H 2025), multi-dosing initiated in RestorAATion-2 (WVE-006, AATD; multi-dose data in 2025), FORWARD-53 48-week data and regulatory feedback targeted in 1Q 2025, and WVE-003 Phase 2/3 IND planned for 2H 2025.
• Strategic validation: first-ever therapeutic RNA editing in humans (WVE-006) achieved in Oct 2024, with single-dose mean total AAT 10.8 μM and M‑AAT 6.9 μM (≥60% of total) at day 15; durable through day 57.
• Stock reaction catalysts near term: FORWARD-53 48-week dystrophin and regulator feedback (1Q 2025); 2025 multi-dose AATD data; 2H 2025 INLIGHT obesity readout; WVE-003 HD IND (2H 2025).

What Went Well and What Went Wrong

What Went Well

• Returned to profitability with Q4 revenue of $83.7M vs. $29.1M prior-year; net income of $29.3M vs. ($16.3M) prior-year; cash runway into 2027.
• Landmark modality validation: “first-ever clinical demonstration of RNA editing in humans” with WVE‑006, achieving total AAT of 10.8 μM and M‑AAT 6.9 μM after a single 200 mg dose, with durability to day 57.
• Pipeline momentum and strategic positioning: “WVE-007…designed to drive weight reduction…with doses just once or twice a year,” highlighting differentiation vs. GLP‑1s; “2024 was an exceptional year for Wave”.

What Went Wrong

• Operating spend rose y/y: R&D $44.6M vs. $34.1M (Q4), G&A $16.1M vs. $13.7M (Q4); full-year net loss widened to $97.0M (2024) from $57.5M (2023).
• Prior quarter volatility: Q3 revenue was negative ($7.7M) due to non-cash timing adjustments under revenue recognition; net loss ($61.8M) in Q3 2024.
• No quantitative 2025 P&L guidance; milestone timing remains the focus (clinical catalysts rather than financial targets).

Transcript

Operator (participant)

Good morning and welcome to the Wave Life Sciences Fourth Quarter and Full Year 2024 Earnings Conference Call. At this time, all participants are on a listen-only mode. As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rausch, Vice President of Investor Relations and Corporate Affairs. Please go ahead.

Kate Rausch (VP of Investor Relations and Corporate Affairs)

Thank you, Operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our Fourth Quarter and Full Year 2024 Financial Results and recent business pilots, including progress updates for obesity and AATD clinical trials. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Erik Ingelsson, Chief Scientific Officer; and Kyle Moran, Chief Financial Officer. The press release issued this morning is available on the investor section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements.

The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filing. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Paul Bolno (President and CEO)

Thanks, Kate. Good morning, and thank you all for joining us on today's call. Over the past decade, we have been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health, and 2024 was an incredibly important year for Wave in realizing this vision. We announced positive data supporting our AATD, DMD, and HD clinical programs, de-risked an entirely new modality in the clinic with RNA editing, and expanded our pipeline with novel, high-impact programs that have potential to address millions of patients. We have carried this strong momentum into 2025 with the advancement of WVE-007, our Galnac siRNA for obesity, to the clinic, and our consistent execution has kept us on track to deliver on key milestones for each program this year. I'll start today by discussing the progress we've made advancing WVE-007 for obesity.

I'd first like to acknowledge that today, March 4th, is World Obesity Day, and this year, the community is highlighting ways to take action to reduce the burden of obesity and related chronic illnesses. At Wave, we are engaged with individuals living with obesity as well as clinicians, so we can do our part to combat disease stigma and deliver healthier futures for this community. In these conversations, the opportunity for healthy, sustainable weight loss with our inhibin E silencing approach is resonating. Enabled by our best-in-class siRNA technology, we believe WVE-007 has the potential to lead the next frontier in obesity treatment for more than 1 billion people living with obesity globally. While GLP-1s are rapidly becoming standard of care among weight loss therapeutics, their use is often limited by frequent dosing, loss of muscle mass, poor tolerability, and high discontinuation rates.

We believe WVE-007 is uniquely positioned to provide a best-in-class approach that addresses these limitations. It is designed to drive weight reduction through an entirely unique mechanism of action that induces fat burning without impacting muscle mass with doses just once or twice a year. Our preclinical data on WVE-007 have not only demonstrated its potential as a frontline treatment option but have shown synergies with GLP-1s, including as an add-on for individuals requiring greater weight loss or who cannot tolerate higher doses of GLP-1s. We are also excited about WVE-007's potential as an off-ramp to GLP-1s, enabling long-term healthy weight maintenance with just once or twice yearly dosing. This maintenance approach would avoid the weight regain that is common when discontinuing GLP-1s and the associated metabolic risk of weight cycling.

Dosing is ongoing in our in-lite clinical trial of WVE-007 for adults living with obesity and overweight, and I'm pleased to say that we have already completed enrollment in the first cohort. We expect to deliver initial data from the trial in the second half of this year, which will include safety, tolerability, and biomarkers reflective of healthy weight loss. Turning to alpha-1 antitrypsin deficiency and WVE-006, our Galnac RNA editing oligonucleotide, or AMER, WVE-006 has the potential to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dosed therapeutic. We do not require IV-administered LFPs or complex delivery vehicles like other treatments in development, and our approach vastly differs from DNA editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and indels.

Our restoration clinical program started with healthy volunteers, and we have now completed all planned cohorts of both single and multi-dosing at dose levels higher than those planned for any cohort in the patient study. In our AATD patient study called Restoration 2, last year, we delivered a breakthrough in RNA medicines with the first-ever clinical demonstration of RNA editing in humans with WVE-006. In our 200 mg cohort, we observed mean 6.9 micromolar of circulating M-AAT and 10.8 micromolar of total AAT two weeks post-single dose in the first two patients in the study, and observed increases in AAT from baseline as early as day three and as late as day 57, an impressive durability of effect. 006 was well tolerated with a favorable safety profile, including the completed Restoration 1 clinical trial of healthy volunteers.

Since this announcement, we have seen a surge in enrollment and demand among clinicians and patients to participate in the study. Multi-dosing is underway in the 200 mg cohort where patients are receiving WVE-006 every other week, and our preclinical and clinical data support potential for extended dosing intervals in subsequent cohorts. We have also initiated the second single-dose cohort at 400 mg, and we believe this higher single-dose cohort coupled with the multi-dose 200 mg cohort will give us meaningful insights into extending the dosing interval. Looking ahead, we will have data from the full first cohort in 2025, including the complete single-dose and multi-dose portions. We also plan to share data from the 400 mg single-dose cohort this year. These data will further inform the therapeutic potential of WVE-006 and our pipeline of RNA editing programs. Behind 006, we're advancing a wholly owned discovery pipeline addressing both hepatic and extrahepatic targets.

We unveiled three of these programs at our research day last year, which collectively provide the potential to address upwards of 10 million patients. As the year progresses, we plan on sharing new preclinical data from our hepatic and extrahepatic RNA editing programs with the goal of initiating clinical development of additional programs in 2026. In Duchenne muscular dystrophy, all muscle biopsies have been collected, and we are on track to deliver 48-week data from our FORWARD-53 clinical trial by the end of this month. In the interim readout last year, we demonstrated WVE-N531's potential to be a best-in-class therapeutic for up to 10% of the boys living with DMD amenable to exon 53 skipping.

We observed highly consistent mean muscle content-adjusted dystrophin of 9%, evidence of improved muscle health, muscle concentrations that support monthly dosing intervals, and distribution to myogenic stem cells, the progenitor cells for new myoblasts that give rise to new myocytes and ultimately aid in skeletal muscle regeneration. Importantly, we also observed a safe and well-tolerated profile. DMD is a devastating disease, and there is an urgent need for more effective and safe therapeutic options for patients. We frequently hear from caregivers about the burden of weekly IV dosing and the need for therapies that can distribute to the heart and diaphragm and reach stem cells, which would enhance functional benefit, improve quality of life, and ultimately extend survival. The upcoming 48-week data will include dystrophin from muscle biopsies, functional measures, as well as safety and tolerability.

We are also on track to deliver feedback from regulators by the end of the month. As a reminder, we have previously shared data from our portfolio of additional exons and pending positive updates on N531. We plan to advance a pipeline of oligonucleotides that addresses up to 40% of boys living with DMD, supported by our best-in-class muscle delivery. Finally, turning to WVE-003, our first-in-class allele-selective oligonucleotide for the treatment of Huntington's disease. HD impacts more than 200,000 people in the U.S. and Europe alone, and there are no disease-modifying therapies available. The disease is devastating, sometimes compared to having Alzheimer's, Parkinson's, and ALS all at once, and is an autosomal dominant genetic disease that impacts multiple generations of family members. For more than 10 years, we have been committed to the HD community and to using our platform's exquisite specificity and unique chemistry to pioneer allele-selective therapeutics.

By reducing mutant Huntington at the mRNA and protein level, WVE-003 addresses the underlying drivers of neurodegeneration. In addition, by sparing wild-type Huntington protein, which is critical to the health of the central nervous system, WVE-003 is uniquely positioned to address the full spectrum of HD, from the early asymptomatic stage through the onset of symptoms and beyond. It is only through our platform's specificity of stereochemical control and best-in-class chemistry that allele-selective silencing became possible in patients. Just last week, I attended the annual CHDI conference where our team had the opportunity to share our select HD clinical results and our plan to accelerate development of WVE-003 by using caudate atrophy as a primary endpoint, a known imaging marker that is potentially predictive of clinical outcomes.

In addition to our podium and poster presentations, we had dozens of great conversations with HD researchers and advocates and heard enormous enthusiasm for WVE-003 and our leadership in allele-selective silencing. As a reminder, data from our select HD trial showed potent and durable mutant Huntington reductions of up to 46% and preservation of the wild-type Huntington with just three doses of WVEWVE-003. Importantly, there was a statistically significant correlation between allele-selective mutant Huntington reductions and slowing of caudate atrophy, marking the first time such a correlation has been observed in Huntington's disease. Caudate is part of the striatum and one of the primary areas where HD manifests in the brain.

With atrophy beginning many years before symptom onset and continuing at a steady rate of decline of about 2%-4% per year, correlations have been shown between caudate loss and clinical outcomes, and at the start of the year, we shared some of our own internal analyses supporting such a correlation. Specifically, we looked at natural history data sets, including Track and Predict HD, which showed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with a delay of onset and disability by more than seven and a half years. This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting the rate of caudate atrophy as a primary endpoint for an efficient clinical trial.

These data, along with the full clinical results from select HD, were both part of our engagement with FDA last year that led to supportive initial feedback. Preparation is ongoing for a global potentially registrational phase 2/3 study of WVE-003 in adults with SNP3 and HD using caudate as a primary endpoint, and we remain on track to submit clinical trial applications, including an IND application for this phase 2/3 study in the second half of this year. In the interim, we've continued to receive substantial engagement in HD, including from potential strategic partners, and look forward to sharing more details on trial design and our path forward as the year progresses. With that, I'll now turn the call over to Erik to share more detail on Inhibin E and provide an update on our emerging pipeline.

Erik Ingelsson (Chief Scientific Officer)

Thank you, Paul, and thank you to everyone joining us on the call today.

As some of you may know, I spent the first part of my career as a physician scientist focusing on obesity and autocrine metabolic diseases, last as a professor of medicine at Stanford, then five years at GSK as head of human genetics, genomic science, and later target discovery across all therapeutic areas before joining Wave last spring. For all of these reasons, I'm incredibly excited to talk about our Inhibin E program, our obesity program with strong support from human genetics. The benefits of such support should not be underestimated, as therapeutic targets supported by human genetics are on average associated with a two- to four-times higher probability of success in drug development when compared to targets without any genetic evidence. Inhibin E is a gene predominantly expressed in liver that produces a hepatocyte activin E. Activin E is secreted from liver and binds to its receptor ALK7 in adipose tissue.

In light of omnipresence of energy-dense food, liver inhibin E mRNA is upregulated, resulting in higher circulating activin E levels due to a maladaptive response, and this promotes fat storage and an increase of abdominal obesity. We chose to target the ligand inhibin E for several reasons. First, using our best-in-class oligonucleotide chemistry to turn off protein production directly at the upstream source is the most efficient way to downregulate activity of this ligand receptor pair. Second, Galnac conjugates allow for a highly specific and efficient targeting to liver cells. Inhibin E silencing leads to lower activin E levels, resulting in higher adipose-like polycytes, thereby decreased abdominal obesity, ultimately leading to healthy weight loss and an improved cardiometabolic profile.

Several large human genetic studies have found that carriers of heterozygous loss-of-function variants in the Inhibin E gene have favorable metabolic profiles, including reduced abdominal obesity in visceral fat, serum triglycerides, ApoB, fasting glucose, HbA1c, and decreases in several measures of liver disease, specifically ALT, corrected T1, an MRI measure of liver inflammation and fibrosis, and lower non-alcoholic fatty liver disease activity score. Importantly, these carriers also have reduced risk of type 2 diabetes and coronary heart disease. Essentially, the outcome study has already been done using Nature's experiment, which also supports the therapeutic threshold of 50% silencing of Inhibin E mRNA. In addition to genetic studies and our convincing preclinical data, recent internal work has demonstrated a strong correlation of circulating Activin E levels with BMI in blood samples from healthy individuals, providing an additional confirmation of the importance of this mechanism in driving obesity in humans.

As we've seen over the past several years, there have been incredible efforts to develop new therapies in the obesity space, which treat the underlying causes of disease and subsequently drive meaningful outcomes for people living with obesity. It is important to step back and examine the approach for our inhibin E Galnac siRNA within the broader context of current treatments, such as GLP-1 agonists and other therapies in development. Although transformational for obesity medicine, GLP-1 drugs are associated with many disadvantages as already mentioned by Paul. Several of these concerns have been highlighted recently, including in draft guidance from FDA earlier this year on developing therapies for weight reduction, which emphasized the agency's focus on establishing study standards that focus on sustained fat loss as opposed to pound-by-pound weight loss, which also involves shrinking muscle mass.

WVE-007 leverages an orthogonal approach from GLP-1s, focusing on peripheral action directly on fat tissue rather than a centrally acting appetite regulation. Not only does this mean that we sidestep disadvantages of GLP-1s, but it also opens up opportunities to position our therapy in relation to centrally acting drugs as an alternative, addition, or as an off-ramp, three use cases supported by preclinical data that we presented at our research day last fall. Our first in-human study of WVE-007 is called In Life. The study is designed to assess safety, tolerability, pharmacokinetics, biomarkers for target engagement, body weight and composition, and other measures of metabolic health. The single-ascending dose portion of the trial in adults living with overweight or obesity is underway, and as Paul shared earlier, the first cohort is already fully enrolled.

We're very excited by the progress we've made bringing this unique and transformative approach into the clinic and look forward to sharing data from the trial in the second half of this year. Now, turning to our emerging pipeline of RNA editing programs, we're continuing to advance WVE-006 in the phase 1b/2a RESTORE-2 study in patients with AATD who have the homozygous Pi*Z mutation. Our initial proof of mechanism data demonstrated impressive potency and durability of effect with WVE-006. Our expected data later this year will assess the ability of 006 to restore healthy M-AAT protein levels with multiple doses, as well as at higher dose level. These data will also provide valuable learnings for our broader RNA editing pipeline, which we continue to advance towards the clinic.

Last year, we shared preclinical data on three of our programs leveraging RNA editing, which are wholly owned and built on our learnings from WVE-006. All three programs are strongly supported by human genetics and offer novel ways to treat diseases in areas of high unmet need. These programs also feature readily accessible biomarkers and approaches to assess pharmacodynamics along with established regulatory paths. As with WVE-006, they leverage Galnac conjugation for efficient delivery to liver. Our PLN3 program aims to correct the PNPLA3 I148M variant to revert homozygous carriers with liver disease to the heterozygous state, which we expect will dramatically decrease steatosis and fibrosis in I148M-driven liver disease. This program includes a large genetically defined population of 9 million people in the U.S. and Europe that are not served by PNPLA3 silencing or by other therapies in development.

Together, our LDL-R and ApoB programs comprise a comprehensive package designed to substantially lower LDL cholesterol among people with familial hypercholesterolemia, or FH. Both programs apply RNA editing technology, aiming to upregulate LDL-R and to correct the dominant ApoB mutation, respectively. Fewer than 50% of people living with heterozygous FH reach their treatment goals with current options, including statins and PCSK9 inhibitors, and our early data indicates that LDL-R upregulation and ApoB correction could result in over 90% of these individuals reaching their treatment goal. This initial disease indication of FH includes 1 million people in the U.S. and Europe. Additionally, our LDL-R upregulation approach has massive upside expansion opportunities for people with statin intolerance or prior cardiovascular disease with poorly controlled LDL cholesterol, two groups that comprise over 30 million people in the U.S. and Europe combined.

We anticipate sharing new preclinical data from hepatic as well as extrahepatic programs this year, and we expect to initiate clinical development of multiple RNA editing programs in 2026. With that, I'd like to turn the call over to Kyle to provide an update on our financials. Kyle.

Kyle Moran (CFO)

Thanks, Erik Our revenue for fourth quarter and full year 2024 was $83.7 million and $108.3 million, respectively, compared to $29.1 million and $113.3 million in the prior year, quarter, and year. The quarter-over-quarter increase was driven primarily by the recognition of the remainder of the deferred revenue under our Takeda collaboration. Research and development expenses were $44.6 million in the fourth quarter of 2024, as compared to $34.1 million in the same period in 2023. Research and development expenses for the full year were $159.7 million in 2024, as compared to $130.0 million in 2023.

This increase was primarily driven by spending for our Inhibin E program, along with our AATD and DMD programs. Our G&A expenses were $16.1 million for the fourth quarter of 2024, as compared to $13.7 million in the prior year quarter, and $59 million for the full year of 2024, as compared to $51.3 million in 2023. Our net income was $29 million for the fourth quarter of 2024, as compared to a net loss of $16.3 million in the prior year quarter. Net loss for the full year was $96.7 million for 2024, as compared to $57.5 million in 2023. We ended the year with $302.1 million in cash and cash equivalents, compared to $200.4 million as of December 31, 2023. The increase in cash year over year is primarily due to our financing proceeds and the receipt of milestone payments and research funding from GSK.

We expect that our current cash and cash equivalents will be sufficient to fund operations into 2027. It's important to note the potential future milestones and other payments to Wave under our GSK collaboration are not included in our cash runway. I'll now turn the call back over to Paul for closing remarks.

Paul Bolno (President and CEO)

Thank you, Kyle. We're off to an incredible start in 2025 and are looking forward to multiple value-accretive inflection points ahead with expected milestones across all four of our clinical programs and data from our growing RNA editing pipeline. With that, I'll turn it over to the operator for Q&A. Operator.

Operator (participant)

Thank you. Ladies and gentlemen, if you wish to ask a question at this time, you will need to press star one one on your telephone and wait for your name to be announced. If you wish to withdraw your question, you may press star one one again.

Please stand by while we compile the Q&A roster. Now, first question coming from the line of Ron Feiner with J.P. Morgan. Your line is now open.

Ron Feiner (Equity Research Associate)

Hi, guys. This is Ron, for Erik. We were hoping to ask about WVE-006. If you can give us a little bit more information on the level of protein we should expect at baseline at the readout. I know that at the top line, the news that you put out earlier, the baseline was zero, but kind of looking at other clinical trials, such as augmentation therapy, the baseline is closer to six, if that's for the total, and about half that for the functional. So just kind of trying to get level set on that. Thanks.

Paul Bolno (President and CEO)

Yeah, thank you.

I mean, if you remember, the baseline was below the lower limit of detection on the assay, but I think stepping back as we look forward, we're highly encouraged that at the starting point of a single dose, the lowest single dose at 200, we saw what would be therapeutically relevant levels of not just total AAT, so that was the 10.8 of the 11 micromolar. I think the most important thing for people to follow as we continue to generate our data, as others generate data, is to really be tracking the M protein levels across studies. That M protein level is important because that is definitively zero. ZZ patients who are entering these studies don't make any M-AAT protein.

If we continue to track M-AAT protein levels, and safe to imagine that over 60% of the protein we saw at the M level was, sorry, at the total level was M protein, that's highly indicative of the mechanism of action of editing. It's the best way to benchmark across programs in terms of the impact the therapeutics are having on editing efficiencies and protein generation, and what should be followed to be consistent. I say that because while historically we've tracked as an industry total AAT levels in the field of IV protein replacement, in editing and correction, one of the things that we saw preclinically was that with time, you see a reduction of aggregates. If you have alpha-1 antitrypsin, these protein aggregates breaking up, they also go into serum.

You can have changes in levels of serum total protein over time that are coming from a variety of sources, those that are directly related to the editing and those related to the protein coming out through the aggregate. The most consistent way to follow editing efficiency is M protein because it is zero in the ZZ patients.

Ron Feiner (Equity Research Associate)

Great. Thanks, Maybe just one more on 007. When we are doing DEXA scanning, do we expect the pattern of lean muscle mass change as proportional or absolute to mirror that of the weight loss? How often are you going to do DEXA scanning compared to weight measurements?

Paul Bolno (President and CEO)

Yeah, we haven't broken out when the DEXA scans are coming in those intervals, but I think to your point, the importance of adding DEXA scan is to really replicate what we saw in preclinical models, which is that weight loss that we saw, definitive weight loss, was coming off of fat. It was all fat loss with no change in muscle mass in the preclinical experiments across multiple systems where we've run that single dose combination and on the withdrawal study. We have multiple examples of preserving muscle sparing with fat lowering. To your point, using DEXA scanning as part of that study will enable us to use that as one of the biomarkers that we can evaluate in healthy, sustainable weight loss in the clinic in the study.

Ron Feiner (Equity Research Associate)

Just maybe one short one. What signal from the DEXA scan would be indicative of a healthier weight loss versus a pattern with GLP-1s? Thanks.

Paul Bolno (President and CEO)

Yeah, we have not shared that. What I would kind of share is we'll have multiple opportunities to add DEXA scans across the study to give a dynamic range with which we can show that.

Ron Feiner (Equity Research Associate)

Great. Thank you so much, guys.

Operator (participant)

Thank you. Now, next question coming from the line of Salim Syed with Mizuho Group, your line is now open.

Salim Syed (Managing Director, Senior Biotechnology Analyst)

Great. Good morning, guys. Thanks for the questions. Paul, maybe just a few from us on DMD since we're getting that readout pretty soon here. Can you just confirm for us, are the discussions being had with the 48-week data, the discussions with regulators being had with the 48-week data, or is it just the 24-week?

Could you perhaps, just as we get closer here, bookend the scenarios that we should be considering coming out on this readout? Just two quick clarifications here. Just remind us how much PMO switchers, if that's even a consideration in this current data set. Also, just as you're kind of considering with the current data that you have in hand, just your pharmacoeconomic work, how you're preliminary thinking about pricing here. Thank you.

Paul Bolno (President and CEO)

Yeah, no, thank you for the questions. As you pointed out, we're on the precipice of this data. One, what's been consistent was that the agency is being engaged around our 24-week data, the data we had shared previously. Obviously, we'll continue to have these data as we move forward, but the data was from the existing data sets that we have.

As I mentioned, we anticipate having that feedback in line with the data from the 48-week study. We will be able to give an update both on the regulatory interactions as well as the data from the study. As it relates to—sorry, Salim, there were a couple there, so I want to make sure we hit each one of those. As we think about the variety of scenarios coming out of this, I mean, I think one of the things that we've seen is the most consistent highest level of dystrophin that's been seen before, the 9%. If we think about that consistency and that magnitude, I think we're going to learn a lot about what a subsequent six months staying on the same dosing regimen is going to do to dystrophin kinetics.

I think there's the opportunity to understand what happens with stabilization and plateauing of dystrophin, or frankly, increasing in dystrophin. We're going to be able to assess that over the additional six months of dosing. I think the other thing that's going to be important with further dosing is we already saw at the initial study was improvement in muscle repair, right? We saw reductions in CKs. We saw muscle health improvement, getting to those regenerative stem cells. A whole variety of features of improvement of muscle health. What's going to be important to us as well is we'll also be assessing that muscle architecture over the subsequent six months. Again, more opportunities to look at the impact of improvement in muscle health, muscle repair. Lastly, and importantly, being able to assess clinical measurements.

While not powered for statistically significant clinical outcome measurements, it's still a relatively small study, I think we do expect to observe trends. Being able to look at 95% stride velocity, being able to look at time to ride, and other sensitive markers will give us that opportunity to assess the translation of that improvement in dystrophin to muscle health and muscle integrity, ultimately to the impact on clinical measurements. We have done a number of early discussions and do see a substantial opportunity in PMO switchers, both in our engagement with clinicians and patients. We also know that a substantial portion of the Exon 53 patients are not on therapies. There is an opportunity not just to switch those who are currently on therapies to a less frequent regimen with potential higher dystrophin and opportunities there without a change in safety risk-benefit profile.

We see that as a very important opportunity on switching, but we do know that there's a large opportunity on patients who are not on existing therapies. At this stage, we have not yet commented on our pharmacoeconomic analyses and pricing funds.

Salim Syed (Managing Director, Senior Biotechnology Analyst)

Okay, perfect. Super helpful. Thanks so much.

Paul Bolno (President and CEO)

Thank you.

Operator (participant)

Thank you. Our next question coming from the line of Joon Lee with Truist Securities, your line is now open.

Joon Lee (Managing Director, Senior Biotech Analyst)

Hey, congrats on the progress, and thanks for taking our questions. Correct me if I'm wrong, but our understanding is that pending outcome of the meeting PTC is having with the FDA in second quarter, there is a chance that Huntingtin Lowering may be deemed an adequate surrogate endpoint, reasonably likely to predict clinical outcome. If that is the case, would you still proceed with the MRI as a primary endpoint? I have a quick follow-up.

Paul Bolno (President and CEO)

Yes. I think it's an important if, but yes, I think if they were to demonstrate data along clinical measurements correlating with mutant huntingtin and the FDA were willing to accept that data as a clinical surrogate biomarker for Huntington's disease, meaning that mutant huntingtin lowering could be associated as a reasonably likely to predict clinical benefit, and the FDA were to make that an endpoint, we're in a position to file off of our earlier data. We have placebo-controlled data with the highest, I should say, the most substantial lowering of mutant huntingtin that's been seen to date at 46% lowering, and on top of mutant huntingtin lowering, spares wild type, which we know is an important indicator to clinicians, patients, but also to the agency itself.

We would deem that existing data set substantial to file and view the subsequent studies we run as confirmatory and make those changes. If that changes at a regulatory endpoint, it's beneficial for the field and for us in particular.

Joon Lee (Managing Director, Senior Biotech Analyst)

Great. You mentioned Huntington prevalence of more than 200,000 in the U.S. and Europe alone, which is higher than the 50,000-60,000 historically cited by other companies. What changed? What kind of data are you looking at that tells you that the opportunity here might be much bigger than previously thought?

Paul Bolno (President and CEO)

I think historically, as numbers get cited in early data sets, they tend to oftentimes reflect a symptomatic HD, so patients who move to the diagnosis clinically on HD.

I think, again, one of the main advantages of why we see allele-specific silencing is so critical in the disease treatment paradigm for Huntington's disease is that ability to move into that early setting. If we think about the work that was done over the last year by the Huntington's research community in restaging Huntington's disease, we used to have a designation between pre-manifest and manifest as kind of a bifurcation. What's really been done in that restaging is realizing that Huntington's disease starts well before the onset of symptoms, and that you can have substantial changes in caudate on measurement on MRI before the onset of symptoms occur where a patient would have historically been diagnosed with Huntington's disease.

As we take that opportunity to say, if you have an allele-specific therapy, meaning you can treat earlier in the disease setting, knock out the bad protein well before you get neurodegeneration and preserve wild type protein so you do not exacerbate the onset of disease, the real opportunity in Huntington is to move early in the disease setting to genetic diagnosis. I think one of the things we will all learn in the HD community is as more therapies continue to come forward and genetic testing continues to increase, the propensity and incidence of Huntington's may be well underpredicted based on the current diagnostic criteria.

Joon Lee (Managing Director, Senior Biotech Analyst)

Great. Thank you.

Paul Bolno (President and CEO)

Thank you.

Operator (participant)

Thank you. Next question coming from the line of Joe Swartz with Leerink Partners, your line is now open.

Joe Schwartz (Senior Managing Director)

Great. Thanks very much.

I was wondering, how should we think about how the effect of WVE-006 could look after multiple doses of 200 milligrams? Can you share any general insights that you have from your preclinical healthy volunteer or modeling work so that we can appreciate how the kinetics might evolve from the strong single-dose data you reported last year?

Paul Bolno (President and CEO)

Yeah. I mean, it's data not only that we have from 006, but with PN chemistry across multiple formats. What we've seen is every time we've gone from single doses to multi-doses, we've seen higher intracellular retention of drug translating to improvements in efficiency. As we said, and thank you for acknowledging, with the early data from the single dose, we see already a substantial uptick in protein production. We expect with multiple doses for that not just to be sustained, but actually to be increased.

The opportunity also exists. This is important as we think about the future dosing regimens for the study, as we have seen consistently with multi-dosing also extension and durability, meaning drug stays in. It is not just drug into the cell, it is retention, meaning decreasing drug out, and therefore improving that potency and durability portion. We are going to learn two things from the 200 mg multi-doses. One is what continues to happen on the protein dynamics, but importantly, we are also going to see what happens with that durability. It is why this 400 mg cohort is important because imagine we already saw the 200 mg cohort, which is therapeutically relevant levels of M-AAT protein. That next window that we will get on the dose response between 200-400 will be really important.

That data, so that amplitude data, and we've said this before, the amplitude data between single doses and what happens with the multi-dose will continue to refine our modeling as we think about the prediction of the multi-dose frequency in cohort two, and then ultimately what the design of cohort three is that would lead to a potentially registration study.

Joe Schwartz (Senior Managing Director)

Okay. Thanks. For WVE-007, how long will patients be treated by the time you share data this year? Do you hope to match the total weight loss effect of GLP-1 therapy at a similar time point, recognizing that these would be cross-trial comparisons, of course? Should we focus on the amount of non-lean body mass changes given this is a different mechanism?

Paul Bolno (President and CEO)

Absolutely. We haven't provided the cutoff point yet. We'll continue to run the study, and we'll provide data from the study.

It is fair to say, as you think about the data from the single dose and thinking about the impressive durability of the opportunity at 6-month-month-12-month durability, that the single-dose data is really reflective of what you would expect to see with long-term treatment. Pre-clinically, we saw weight loss similar to the GLP-1s and semaglutide. I think the opportunity exists to follow weight. I think what is going to be really important, as you brought up, is really to delineate this concept of weight loss in a very broad stroke category of muscle and fat to really be able to break that down into fat loss. I think that is what we want to see in the upcoming study, those changes in body composition in addition to biomarker data. I think the totality of that data will distinguish it from GLP-1.

I think where we are currently is every medicine is put up against the same because it's very much similar classes and what's that impact to overarching weight loss at the expense of muscle with the properties that are very similar. I think the full opportunity in this initial data set is really to distinguish this unique category of medicines from that GLP-1, where we're not doing essentially chemical starvation. We're driving a metabolic shift in phenotype. We believe that these data will be supportive in addressing that thesis and being able to demonstrate the difference of inhibin E as an independent mechanism for healthy sustainable weight loss.

Joe Schwartz (Senior Managing Director)

Thanks for the insights.

Paul Bolno (President and CEO)

Thank you.

Operator (participant)

Thank you. Our next question coming from the line of Roger Song with Jefferies, your line is now open.

Roger Song (Senior Equity Research Analyst)

Great. Thanks for the thanks for the, I think, the question.

A couple of questions on us. The first one is for the AATD. I think, Paul, you mentioned you're expecting the higher dose on the multi-dose and the higher dose may be able to increase the M protein production correction and then total protein production. My question is, do we know the correlation between the M protein level and the total protein level versus the liver and the lung function? Given so far we only have the replacement therapy, but we have some other genetic medicine try to increase the level a little bit higher than what you have seen in the set 200-milligram dose. Thank you.

Paul Bolno (President and CEO)

Yeah. I mean, it's a wonderful question going back to just the basis for RNA editing.

If we think about the basis that drove how 11 micromolar, which we all kind of cite and has been subsequently, there's been discussions around with IV protein replacement where that level setting, we have to kind of remember how we got to that level. Your question about what's required for lung and liver production. If we do think about the heterozygous phenotype, that 50% level of correction, the nadir of that was about 11 micromolar. If you look at the kind of lower limits of that heterozygous population, that was the benchmark for setting that level of total protein.

It was really set off a dynamic range of essentially people who are walking around with one copy of a healthy alpha-1 antitrypsin protein and the other within this folded copy, which isn't necessarily an apples-to-apples when you imagine when you're adding on protein on top of that to set a level with replacement. Those patients still have a reserve of being able to make 50% M protein and production. When we take this back to what we're doing in the field of editing, the thesis was really, could we restore that heterozygous population back where we know that by doing that, that we could actually have and rely on the human clinical data that shows that those heterozygous patients have protection of lung function and liver function.

What was encouraging too, when we think about the benefit of RNA editing, is by editing in the promoter region, we're really restoring that functional activity back to these patients. We do need to think about RNA editing as a different category than how we think about protein replacement because we're really restoring that function back to these patients. We went back to our clinical data. If you think about what we've already seen, at 11 micromolar of total protein and over 60% of that being M protein, we've essentially recapitulated what you'd expect to see in that heterozygous patient. We're encouraged to see what happens over time with repeat dosing and where the levels of protein can go, also M protein, but also looking at the durability.

Again, it's going to be great to see what happens as we increase that total level of protein and what that level of correction can continue to be. I think the key for us still remains that if you follow the translation of turning ZZ patients, again, who have no baseline level of M protein, and be able to correct them back to a heterozygous phenotype, looking at M protein will enable us to be able to understand how well we can correct that as a field in humans. We're highly encouraged by our initial clinical data.

Roger Song (Senior Equity Research Analyst)

Thank you. Maybe just a quick one for DMD. Understanding you're talking with the FDA and then for the potential regulatory path. Understanding you try also maybe be able to do some umbrella kind of a registrational trial.

Would that be the topic we will get the update this quarter, or there will be a coming a little bit later? Thank you.

Paul Bolno (President and CEO)

No, thank you. I mean, as we said, the discussion encompassed the data from the initial interim data from the 24 weeks. Importantly, as we also said, it's about what's next for the program in terms of accelerated registration and confirmatory study design. We will be able to provide in totality an update as part of these data sets on next steps for the program.

Roger Song (Senior Equity Research Analyst)

Thank you.

Paul Bolno (President and CEO)

Thank you.

Operator (participant)

Thank you. Our next question coming from the line of Luca Issi with RBC Capital Markets. Your line is now open.

Oh, great. Thanks so much for taking our question. This is Lisa. I'm for Luca. Just wondering, how should we think about dosing for RNA editing versus DNA editing versus siRNA?

It looks like your second dose for AATD is already at 400 milligrams versus Intellia is using an eight times lower dose in their pivotal study with HAE at about 50 milligrams. And Alnylam is approved for TTR at a dose 16 times lower at 25 milligrams. Appreciate that these are totally different mechanisms of action, but how should we think about total drug exposure here for ADAR? Is there any risk on the safety side with going to such high doses? Thanks so much.

Paul Bolno (President and CEO)

Yeah. I mean, I think one of the things you have to look at is the 200 milligram is lower than in Questran. I think sometimes we have to think about the calculations of doses of milligrams per kilogram and what that is in total drug delivered versus the absolute dose.

We're giving these as absolute doses, not dose per kilogram for patients. Importantly, this is the first time anybody has been exploring ADAR editing to understand the kinetics of the enzyme. What we do realize is the opportunity you have when you bring a whole new mechanism and modality forward and are frankly leading that for the field is the real opportunity to be able to explore the ranges of what's possible. Ultimately, what's important is dose, but dose to establish an efficacy threshold, but also a durability threshold. I mean, if we could be dosing this monthly, quarterly, less frequently, we're going to understand that. There are nuances always across different enzymatic systems. We understand as a field what happens with siRNAs. Although it's important to note, in siRNAs, we're seeing things that are incredibly different than what's been seen with Alnylam before.

I mean, we showed a 30-fold improvement in AGO2 loading over Alnylam, which isn't just translating to better potency. It's translating to radically different durability, the prospects for highly infrequent dosing. That is important to be able to think about the nuances of how does chemistry add to not just a potency quotient, but a durability quotient. I think the opportunity we also have for AATD specifically is to really understand the upper bound. I mean, our initial dose let us get to therapeutic levels within a heterozygous patient population. We're going to understand where one could go even beyond that. I think that opportunity of really being able to explore dose is important. I think the other thing to note is we've gone higher than all anticipated doses, even above the third cohort in the healthy volunteer study.

From a safety perspective, not just preclinical safety, but human clinical safety, we have substantial single and multi-dose human safety data that does let us continue to explore the upper bounds of editing. I think that's going to be important as we set the paradigm for what is good editing going to look like. I think ultimately, dose is less important in the absence of what it's doing. I think we're going to understand a lot between the two and four, but also importantly, what the repeat dosing at 200 does. I think it's going to be an exciting time for the field as we look across modalities and mechanisms at what levels of RNA protein editing and correction are going to be possible.

Got it. Thanks so much, Paul.

Absolutely. Thank you.

Thank you. Our next question is coming from the line of Catherine Novack with Jones Trading, Your line is now open.

Catherine Novack (Director)

Hi. Good morning. Thanks for taking my questions. I just wonder if you can give any more details about the multiple dose cohorts in AATD. How many patients are you anticipating, granularity as to when in 2025 we should expect this? In conjunction with that, thoughts on the M-AAT threshold, understanding that Z protein is not functional, so we're not really looking at total AAT. Do you consider the 20 micromolar M-AAT to be the threshold for success?

Paul Bolno (President and CEO)

Thanks. Yeah. I think stepping back, each cohort, as we said, is eight patients with repeat dosing. We've been very clear with what the number of patients are going to be. That will be the totality of that data set, and they'll have seven doses.

These patients are going to get a substantial amount of medicine repeated, which is going to let us, in a really nice way, look at that translation from single to multi-dose. We'll have that total data set from the single and the multi with which we can look at the dynamic effects of protein production. To your point, which is interesting, is if we remember back to what the established threshold is for the therapeutic activity of a heterozygous patient, so assume 11 micromolar of the nadir, 50% of that is M, and the other part is Z, we're already at 60% edited M protein looking at that total. To your point, we're still going to measure. I don't want anybody—I wasn't sure—we're subject to interpretation. We're still going to show total protein as we do the study.

We'll be able to look at that relative ratio between total protein and then specifically M protein. The reason we highlight M protein is it is critical because the M protein is only, again, produced based on the medicine's ability to edit the transcript. It gives the most insight into editing efficiency, protein production. Therefore, we know that the MZ phenotype is a stable, safe phenotype. Therefore, what we want to do is continue to push those patients towards higher levels of M protein. We have substantial activity at the 200 milligram. We're going to see what that does in repeat dosing. We could reasonably expect to see not just a higher level of that M protein, but really looking at how durable and sustainable that is as we think about dosing regimens.

Catherine Novack (Director)

Got it. Thanks.I had just one more on your thoughts on siRNA obesity targets outside of in hibin, such as GPR 75, for example. Is this something you could explore in conjunction with the inhibin program? Thanks.

Paul Bolno (President and CEO)

Yeah. We think about a whole range of potential ways of using both siRNA as well as editing that could target the field of metabolic disease. GPR 75 is orthogonal. As we've mentioned, we do look at orthogonal approaches to treating obesity. With our siRNA technology, not talking about GPR 75 at the moment, but we've shown substantial durable potent silencing in the CNS with potential for once a year, even potentially less frequently with administration.

We shared that data as part of the data demonstrating and distinguishing differentiation between the state-of-the-art chemistries that are for siRNA and showing, again, how that's different and how we see better potency and durability with our siRNA chemistries, not just with Galnac in the liver, but also in CNS. We are evaluating a number of targets within the metabolic field.

Catherine Novack (Director)

Got it. Thanks very much.

Paul Bolno (President and CEO)

Yes.

Operator (participant)

Thank you. Our next question coming from the line of Ryan Deschner with Raymond James, your line is now open.

Ryan Deschner (VP of Equity Research)

Hi there. Good morning. For the 007 program, what would a late-stage clinical study assessing the therapeutic as more of a maintenance therapy actually look like? What would you anticipate on an initial label to look like for this program regarding positioning as a mono, add-on, or maintenance therapy if successful? Thank you.

Paul Bolno (President and CEO)

Yeah. I mean, we do think a lot about the opportunities. I say more about the single dose and then the maintenance. We are going to be generating that data as part of these data sets. We are going to have a very good sense of the behavior of inhibiting as a single-agent therapy and what level of healthy sustainable we must see and being able to drive that forward into a potentially registrational study. I think the other study that we are excited to engage in, which is, as you alluded to, is that off-ramp. Being able to replicate that study that we have run, it is very feasible to look at patients on GLP-1s that are stable on a GLP-1 and then to be able to dose and withdraw. The designing of those next studies are being planned.

We are thinking about how to conduct those so that they could serve two purposes. Obviously, one, generate really important, meaningful data of how we hope the product potentially be used in clinics, but two, to also support a label for registration for reimbursement. As we think about the total opportunity as both a monotherapy, but very, very important on this off-ramp, I think that's going to be a really interesting study to be running real-time where patients who are going to be currently on those therapies now can be withdrawn and studied in that context in a really substantial way. We have those plans underway.

Ryan Deschner (VP of Equity Research)

Thanks for the question.

Paul Bolno (President and CEO)

Thank you.

Operator (participant)

Thank you. Our last question and Q coming from the line of Madison El-Saadi with B.Y. Lee. Your line is now open.

Madison El-Saadi (Research Analyst)

Hi. Thanks for taking our question. What are your plans for the MDA conference?

Will you host an event around the conference to provide that regulatory update? Then second, on 003, I know you had an updated analysis of CHDI, as you mentioned in your prepared remarks. Just wondering if you could kind of remind us or characterize the previously reported NFL data in terms of change from baseline. Then secondly, how do you see 003's profile relative to the exon one targeted candidates? Thanks.

Paul Bolno (President and CEO)

Yeah. Wonderful. I'll take the MDA question first. While our team has a presentation that was already scheduled to be prepared, the data will not be presented at MDA coming up, I think timing-wise. I think there won't be a separate event around that. We do expect to have the full data as well as our regulatory update by the end of the month.

We do not time, as we historically have always said, we do not time our data releases around conferences, but rather when the data is ready for presentation. As it relates to the 003, and I think this was a great conversation at CHDI, we will take the exon one off the table first because I think there was a lot of discussion. We talked to translational medicine experts about a lot of concerns about the exon one hypothesis. I think a lot of those concerns stem from the fact that when people went back and did the analysis of healthy brains on MRI, so patients who had autopsy but did not have HD and those who did, both sets of patients have exon one. It was not specific for Huntington's disease.

In fact, a lot of the model systems, and I think it's always important, and HD is not unique in this, when you look at translational models to predict activity and what to expect in the clinic, it's always important to do more characterization on the animal mouse models. To date, there's been a lot of changes that happened in these mouse models that don't happen in humans. I should also add that a lot of the data that's being presented around exon one, and there was a presentation, I believe, at the Alnylam R&D Day, actually used Wave allele-specific oligonucleotides that were presented previously. We had shared data that said that our allele-specific oligonucleotides, and this was shared in a CHDI presentation, actually demonstrated a benefit and that that target happened to also coincide with exon one was picked up.

I think what ended up becoming is that that became an exon one study. It was actually, very importantly, an allele-specific oligonucleotide study that we had engaged with and worked with some of the KOLs in the space. We were not referenced in the presentation, but it is important that a lot of the emerging supportive data on exon one are actually being generated with Wave allele-specific oligonucleotides, which, as we would expect, if you reduce mutant Huntington protein and preserve wild types, as we have shown not just in preclinical studies, but ultimately in the clinic, you do see changes and potential benefits. I highlight that around the exon one discussions to date. As it relates to the NFL studies, I think a couple of important things.

One, again, in the full retrospective New England Journal analysis of the Toma Nurse and Generation HD1 study, there was no correlation between NFL and clinical outcomes. It is just an important reminder. We did share the follow-up from our FDA feedback last year, in which we reiterated again that NFL was not the subject of that discussion. We do follow it. It is important that I think everyone in the field is going to measure it and continue to look for those applications. Again, NFL has not correlated with outcome measurements.

Madison El-Saadi (Research Analyst)

Got it. Very helpful.

Paul Bolno (President and CEO)

Thank you.

Operator (participant)

Thank you. I am showing no further questions. I will now turn the call back over to Dr. Paul Bolno for final remarks.

Paul Bolno (President and CEO)

Thank you for joining our call this morning. We look forward to connecting with many of you this month when we expect to share data from Forward 53.

Operator (participant)

Have a great day. This concludes today's conference call. Thank you all for your participation, and you may now disconnect.